The present invention relates to an improved and industrially advantageous process for the preparation of the antidepressant fluoxetine of Formula I 
and its pharmaceutically acceptable salts, preferably hydrochloride.
Chemically, fluoxetine is N-methyl-3-[(4-trifluoromethyl)phenoxy]-3-phenylpropyl amine and is a well known useful antidepressant possessing central nervous system activity. Its pharmacological effect is based on its ability to be a potent and selective brain serotonin re-uptake inhibitor without any influence on the dopamine and norepinephrine systems.
There are several methods known in the literature for the preparation of fluoxetine. One such method is known in U.S. Pat. No. 4,314,081 which claims fluoxetine per se and discloses a process which comprises reducing 3-dimethylaminopropiophenone to yield 3-dimethylamino-1-phenyl-1-propanol. This compound on treatment with thionylchloride and refuluxing the resulting chloro derivative with 4-trifluoromethyl phenol under alkaline conditions for several days to yield N, N-dimethyl-3-[4-(trifluoromethyl) phenoxy]-3-phenyl-propylamine. Selective demethylation in two steps using cyanogen bromide followed by hydrolysis with potassium hydroxide in ethylene glycol at 130xc2x0 C. for about 20 hours give the desired compound fluoxetine of Formula I.
Another process for the preparation of fluoxetine is described in GB Patent No. 2,060,618 which comprises reacting sodium salt of N-methyl-3-hydroxy-3-phenylpropylamine of Formula II 
(formed with sodium hydride in dimethyl sulphoxide) with 1-fluoro4-(trifluoromethyl)benzene of Formula III 
at high temperature.
According to Hungarian Patent No. 207,035, fluoxetine is prepared by the etherification of N-methyl-3-hydroxy-3-phenyl propylamine of Formula II with 1-chloro-4-trifluoromethyl benzene of Formula IV 
in the presence of sodium amide as a base using dimethylsulphoxide as a solvent, whereas U.S. Pat. No. 5,166,437 describes the above etherification step which is carried out in solvents such as N-methyl pyrrolidone or dimethyl sulphoxide in the presence of potassium t-butoxide. U.S. Pat. No. 5,225,585 describes a process which involves use of sodium hydride in dimethylacetamide/toluene mixture in the etherification step.
The process according to PCT application WO 94/00416 also involves the etherification of N-methyl-3-hydroxy-3-phenyl propylamine of Formula II with 1-chloro-4-trifluoromethyl benzene of Formula IV in the presence of potassium hydroxide or sodium hydroxide in DMSO at a temperature between 50-120xc2x0 C. for 4 to 20 hours. We carried out the etherification step in our laboratory as per the teachings of the PCT application WO 94/00416, which took about 24 hours for completion of the reaction and there was a concomitant formation of several impurities during the course of the reaction.
In our hands, we got an impure product (purity xcx9c90%) which needed to be purified to obtain pure or pharmaceutically acceptable grade of fluoxetine hydrochloride. This ultimately resulted into significant loss of yield.
The above mentioned methods described in the prior art for the manufacture of fluoxetine of Formula I suffer several limitations, some of which are discussed below:
The methods require raw material which are highly toxic, explosive and difficult-to-handle at a commercial scale, e.g., cyanogen bromide, sodium hydride, sodium amide, thionyl chloride, potassiumxe2x80x94t-butoxide.
The reaction conditions are unsafe which are burdened with risk of explosion and fire and hence are inconvenient to handle at a commercial scale, namely, the so-called dimsyl sodium formation in the reaction of sodium hydride with dimethyl sulphoxide. Several spontaneous decompositions, explosions and fires have been reported in connection with its preparation (Ref.: Houben-weyl, Vol. 13/1, page 304, G. Thime verlag, stuttgart (1970)].
The processes require limited available and costly raw materials such as 4-(trifluoromethyl)phenol, 1-fluoro-4-(trifluoromethyl)benzene, cyan-ogen bromide, etc.
The reactions take 20 hours to several days for completion.
The process generates a lot of effluent waste and hence is not eco-friendly.
Low overall yield and impure product.
It is an object of the present invention to solve the problems associated with the prior art and to provide an efficient method. According to one aspect of the present invention, there is provided an efficient process for the preparation of fluoxetine of Formula I and its pharmaceutically acceptable salt preferably hydrochloride which provides obvious benefits with respect to economics and convenience to operate at a commercial scale.
More particularly, the present invention relates to a process for the preparation of highly pure (purity more than 99%) fluoxetine of Formula I and its pharmaceutically acceptable acid addition salts, preferably hydrochloride, which comprises reacting N-methyl-3-hydroxy-3-phenyl propylamine of Formula II with 1-chloro-4-(trifluoromethyl)benzene of Formula IV in the presence of alkaline metal hydroxide in sulfolane in the presence of a catalyst.
The suitable alkaline metal hydroxide is selected out of sodium hydroxide and potassium hydroxide. The catalysts used in this invention are poly (ethylene glycol) -6000 and crown ethers.
The amount of solvent is at least 1 part by volume per part of N-methyl-3-hydroxy-3-phenylpropylamine of Formula II. Higher amounts of solvents and generally up to 20 parts by volume may be used. Amounts higher than 20 parts by volume are not useful from an economic point of view because large size reactors would be required.
Generally, the reaction is carried out at a temperature ranging from about 80-130xc2x0 C. preferably, at 90-100xc2x0 C.
The above reaction is efficiently accomplished in less than hour. However, the length of time required will vary depending upon such factors as temperature of reaction, concentration and presence or absence of efficient stirring.
After the reaction is over, the reaction mixture is cooled, a mixture of water and toluene is added. The reaction mixture is acidified with any mineral acid, preferably, hydrochloric acid. Toluene layer is separated and subjected to vacuum distillation to recover crude fluoxetine. Crude fluoxetine is crystallized from ethyl acetate to give the pure fluoxetine hydrochloride.
In the following section a preferred embodiments are described by way of examples to illustrate the process of this invention. However, this is not intended in any way to limit the scope of the present invention.